19-norandrostadienes and method of preparing the same



United States Patent Office 3,211,764 19-NORANDROSTADIENES AND METHOD OF PREPARING THE SAME John Johnston Brown, Pearl River, and Seymour Bernstein, New City, N.Y., 'assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed Sept. 25, 1963, Ser. No. 311,303 4 Claims. (Cl. 260397.45)

This invention relates to new steroid compounds. More particularly, it relates to new 1lii-hydroxy-l9-norandrosta- 4,9(10)-dien-3-ones.

The novel steroid of the present invention may be illustrated by the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, ethynyl and chloroethynyl.

The compounds of this invention are, in general, white crystalline solids, relatively insoluble in water, but soluble in many common organic solvents such as lower alkanols and esters, acetone, dioxane and the like.

The present compounds are preferably prepared by a two-step synthesis comprising the steps: (1) subjecting 21 AS (10),9( ll )-3-one steroid of the formula:

wherein R is as defined above, in solution in a basic solvent such as pyridine, quinoline, or the like, to the oxidative action of air, oxygen or other oxygen source to form an intermediate hydroperoxide of the formula:

wherein R is as defined above; followed by (2) treating said intermediate hydroperoxide with a reducing agent such as, for example, an alkali metal iodide to yield the desired product.

Usually it is not necessary to isolate or purify the intermediate hydroperoxide. In general, the crude intermediate may be treated with an alkali metal iodide reducing agent, sodium iodide being a convenient reducing agent in a solvent, such as acetic acid and a lower alkanol. The final product can then be isolated by conventional techniques and purified by crystallization. In the oxidation step this may be accomplished by stirring the solution of starting material exposed to air at room temperature for two or three days.

3,211,764 Patented Oct. 12, 1965 The compounds of the present invention are useful as hypocholesteremic agents in the treatment of hypercholesteremia and related vascular disorders.

The following examples illustrate in greater detail the preparation of the 17-substituted 11,8-hydroxy-19-norandrosta-4,9( 10)-dien-3-ones.

Example 1.-Preparati0n of 115,] 7 8-dihydr0xy-19-n0ran drama-4,9 (10 -dien-3-0ne 176-hydroxy-19-norandrosta-4,9(10)-dien-3-one is prepared by the method described in J. Am. Chem. Soc. 82, 2402 (1960). p-Toluenesulfonic acid (100 mg.) is added to a solution of 17,8-hydroxy-19-norandrosta-4,9(10)-dien- 3-one (200 mg.) in methanol (4 ml.), methylene chloride (4 ml.) and methyl orthoformate (4 ml.). After 10 minutes pyridine (2 ml.) is added followed by methylene chloride. The mixture is washed with water and dried and the gum obtained by removal of solvent is dissolved in petroleum ether and chromatographed on a synthetic magnesium silicate (10 g.). The gum eluted with 1% acetone in petroleum ether is dissolved in acetone (6 ml.) and dilute sulfuric acid (3 drops; 8% v./v.) is added. After 5 minutes the solution is diluted with water and the mixture is kept in the cold for one hour. The material which has separated is collected, dried and crystallized from acetone-petroleum ether to give 17B-hydroxy-19- norandrosta-5(10),9(11)-dien 3-one as needles mg), melting point about -1l8 C.

A solution of 17,8-hydroxy-l9-norandrosta-5(10),9(11)- dien-3-one (500 mg.) in pyridine (12.5 ml.) is stirred-at room temperature for about three days. Solvent is removed to give crude 1lfi-hydroperoxy-l7fi-hydroxy-19- norandrostal,9(10)-dien-3-one. Sodium iodide (1 g.) is added to a solution of this hydroperoxide in methanol (20 ml.) and acetic acid (10 ml.) and the mixture is kept at room temperature for thirty minutes. Aqueous sodium thiosulfate is added followed by water and the mixture is extracted with methylene chloride. The dried extract is chromatographed on a synthetic magnesium silicate (25 g.) and the material eluted with 25% acetone in methylene chloride is crystallized from acetone-n-hexane to give the above product mg), melting point 184-188 C.

Example 2.Preparati0n of 1 113,1 7fl-dihydr0xy-1 7amethyl-19-n0randr0sta-4,9 (1 0 -dien-3-0me 17B-hydroxy 17a methyl 1-9 norandrosta-4,9(10)- dien-3-one [1. Am. Chem. Soc., 82, 2402 (1960)] is treated as in Example 1 above to give the product l7fl-hydroxy- 17u-methyl-19-norandrosta-5(10),9(l l)-dien-3-one.

A solution of 17fl-hydroxy-l7-a-methyl-19-norandrosta- 5(10),9(1 l)-dien3-one (500 mg.) in pyridine (12.5 ml.) is stirred at room temperature for three days. Solvent is removed to give crude 1lfi-hydroperoxy-l7B-hydroxy-17amethyl 1.9 norandrosta 4,9(10)-dien-3-one which is treated with sodium iodide (1 g.) in methanol (20 ml.) and acetic acid (10 ml.) as described in Example 1. The product, isolated by chromatography as in Example 1 above, is crystallized from acetone-n-hexane. T-he product (200 mg.) has a melting point of 189-l93 C.

Example 3 .Preparation of 11fl,17.,B-dihydr0xy-17achloroethynyl-l 9-n0randr0sta-4,9( I 0 -dien-3-one 17 ot-chloroethynyl 17,8 hydroxy-19-norandrosta 4,9 (10)-dien-3-one ['J. Am. Chem. Soc., 83, 4663 (1961)] is treated as in Example 1 above to give the product 17achloroethynyl 17/3-hydroxy-19-norandrosta-5 10) ,9(11)- dien-3-one.

The latter steriod on stirring at room temperature in pyridine produces the corresponding 11 fi-hydroperoxy 0 derivative which, on treatment with sodium iodide as de- 3 Example 4.Preparatin of 1 1B,17,B-dihydr0.xy-1 70cethynyl-I 9-n0randr0sta-4,9(10)-dien-3-0ne Following the procedure of Example 1 and using as starting material 17a-ethynyl-17/8-hydroxy-l9-norandrosta-S(10),9(11)-dien3-one the product described above is obtained.

We claim:

1. The compound 11B,17/3-dihydroxy-17u-chloroethynyl-19-norandrosta-4,9( 10 -dien-3-one.

2. A method of preparing compounds of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, ethynyl and chloroethynyl which comprises contacting the corresponding 19-norandrosta- (10),9(11)-diene with oxygen to produce llfi-hydroperoxido 19 norandrosta 4,9(l0)-diene, subsequently treating the said llfl-hydroperoxido compound with an alkali metal iodide and recovering said compound therefrom.

3. A method of preparing 1lB,17 3-dihydroxy-19-norandrosta-4,9(10)-dien-3-one which comprises contacting 17/8-hydroxy-l9-norandrosta-5 10) ,9 1 l )-dien-3-one with oxygen in the presence of pyridine, subsequently treating the reaction product, 1lB-hydroperoxido-17fi-hydroxy-19- norandrosta-4,9(10)-diene-3-one with sodium iodide in a solvent and recovering said compound therefrom.

4. A method of preparing 1 1;3,17fl-dihydroxy-17amethyl-19-norandrosta-4,9(10)-dien-3-one which comprises contacting 17/3-hydroxy-Uni-methyl-l9-norandrosta- 5(10),9(ll)-dien-3-one with oxygen in the presence of pyridine, subsequently treating the reaction product, hydroperoxido 17,8-hydroxy-17a-methyl-19-norandrosta- 4,9(10)-diene-3-one with sodium iodide in a solvent and recovering said compound therefrom.

References Cited by the Examiner UNITED STATES PATENTS LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,211,764 October 12, 1965 John Johnston Brown et al.

It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 35 to 43, the formula should appear as shown below instead of as in the patent:

Signed and sealed this 24th day of May 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J, BRENNER Attesting Officer Commissioner of Patent. 

1. THE COMPOUND 11B,17B-DIHYDROXY-17A-CHLOROETHYNYL-19-NORANDROSTA-4,9(10)-DIEN-3-ONE. 